Certain functional interactions between the nervous, endocrine, and immune systems are mediated by cytokines. The pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF) were among the first to be recognized in this regard. A modulator of these cytokines, IL-10, has been shown to have a wide range of activities in the immune system; but little is known about its action in the neuro-immune axis. Recent evidence indicates that IL-10 is expressed in hypothalamus and pituitary and it induces the production of corticotropin (ACTH) from both pituitary and lymphoid cells. Overall, the objective of this application is to determine IL-10's role in neuroendocrine function and in neuro-immune interactions. Furthermore, the production of the highly homologous IL-10 counterpart, viral IL-10 (BCRF1) produced during Epstein-Barr virus infection, provides a clinical relevance for studying alterations or interference of native IL-10 in neuroimmune interactions during pathological processes. Specifically, it is planned to: (1) determine the cellular sites of production of IL-10 and IL-10 receptor in neuroendocrine tissues by immunohistochemistry and in situ PCR; (2) determine IL-10 actions on neuroendocrine tissue by measuring its effects in vitro on cytokine and releasing factor induced hormone production and action; (3) determine if IL-10 is conserved as a common signal molecule by analyzing its effects on hormone and cytokine interactions in lymphocytes; (4) determine how IL-10 alters neuroendocrine function at the cellular level by characterizing intracellular signal transduction pathways that are modulated; (5) determine if viral IL-10 has similar and/or altered activities by comparing it to native IL-10; and, (6) determine if IL-10 acts on the neuro-immune axis in vivo, comparing responses in normal, hypophysectomized and Il-10 deficient mice. Results from this project aim to advance the understanding of how the neuroendocrine system influences and is influenced by others, such as the immune system, which maintains homeostasis and defends/repairs the body's tissues.